The Role of Reductive Stress in the Pathogenesis of Endocrine-Related Metabolic Diseases and Cancer.

Reductive stress (RS), characterized by excessive accumulation of reducing equivalents such as NADH and NADPH, is emerging as a key factor in metabolic disorders and cancer. While oxidative stress (OS) has been widely studied, RS and its complex interplay with endocrine regulation remain less understood. This review explores molecular circuits of bidirectional crosstalk between metabolic hormones and RS, focusing on their role in diabetes, obesity, cardiovascular diseases, and cancer. RS disrupts insulin secretion and signaling, exacerbates metabolic inflammation, and contributes to adipose tissue dysfunction, ultimately promoting insulin resistance. In cardiovascular diseases, RS alters vascular smooth muscle cell function and myocardial metabolism, influencing ischemia-reperfusion injury outcomes. In cancer, RS plays a dual role: it enhances tumor survival by buffering OS and promoting metabolic reprogramming, yet excessive RS can trigger proteotoxicity and mitochondrial dysfunction, leading to apoptosis. Recent studies have identified RS-targeting strategies, including redox-modulating therapies, nanomedicine, and drug repurposing, offering potential for novel treatments. However, challenges remain, particularly in distinguishing physiological RS from pathological conditions and in overcoming therapy-induced resistance. Future research should focus on developing selective RS biomarkers, optimizing therapeutic interventions, and exploring the role of RS in immune and endocrine regulation.